Radiation pneumonitis after intentional or accidental exposure to a radioactive source, is associated with damage or loss of lung endothelial and epithelial cells, the release of cytokines, an accumulation of inflammatory cells within the alveolar spaces, and later, pulmonary fibrosis. It is the goal of this grant proposal to investigate approaches to mitigate radiation-induced lung injury in a large animal model. The agents selected for the study will have different putative mechanisms for mitigating the effect of the ionizing radiation on the lungs. In aim 1, we will determine the local dose of radiation to the lung which predictably induces radiation pneumonitis when administered in combination with total body irradiation. In aim 2, we will evaluate the effect of the study agents at the dose of radiation predicted to induce lung injury in aim 1. First, we will investigate the effect of keratinocyte growth factor (KGF) otherwise known as palifermin on the development of radiation pneumonitis. KGF stimulates type II pneumocytes and in rodents is protective for the lungs after radiation exposure and in other lung injury models. We will then assess the effect of primary bone marrow-derived mesenchymal stem cells (BM-MSC) on the development of radiation pneumonitis. It has been reported that MSC have directed migration to injured tissue and have mitigated tissue injury in models of ischemia or ischemia-reperfusion. MSC are immunomodulatory and may also contribute to the reconstitution of injured lung tissue. Finally, A2A adenosine receptor (AR) agonists will be tested. AR agonists have been shown to induce anti-apoptotic signals in tissue injury models and are anti-inflammatory. In aim 3, the study agent found to be most effective in aim 2 will be tested at an increased dose of radiation to the lung. Preclinical development of effective strategies for the mitigation of radiation-induced lung injury in a large animal model will increase the probability of successful treatment of victims exposed to ionizing radiation from a nuclear weapon or a 'dirty bomb'.